Thyroid Hormones Act as a Timer for the Postnatal Maturation of Parvalbumin Neurons in Mouse Neocortex

Background: A finely tuned balance between excitation and inhibition is essential for proper brain function. Disruptions in the GABAergic system, which alter this equilibrium, are a common feature in various types of neurological disorders. Understanding GABAergic neuron maturation processes is thus currently a major challenge in basic neuroscience. Thyroid hormones (THs) are required for the proper maturation of parvalbumin (PV)-expressing GABAergic interneurons in the mouse neocortex. However, the timeline of this TH action has yet to be elucidated. The aim of the present study was to define better the time window during which THs promote the postnatal maturation of PV neurons in the mouse neocortex. Methods: We used genetically engineered mouse models expressing dominant-negative mutations of the TH nuclear receptor α1 (TRα1). The consequences of blocking TH signaling at different times in development were assessed in PV neurons of the somatosensory cortex, in terms of histology and gene expression. Results: Histological observations in mice revealed that the action of THs during the first three postnatal weeks was necessary to initiate the expression of PV and the elaboration of a specialized extracellular matrix called the perineuronal net (PNN). By contrast, after the third postnatal week, TH action on PV neuron maturation appeared to be somewhat dispensable. Transcriptome analysis of neocortical GABAergic neurons two weeks after birth identified a small set of putative target genes for TRα1. Several of these genes are involved in the postnatal remodeling of the repertoire of ion channels within PV neurons and in the elaboration of PNNs. Conclusions: These data suggest that THs act as a timer to define the temporal boundaries of the critical period of heightened cortical plasticity, which plays a fundamental role in the development of neuronal circuits. Unveiling the molecular underpinnings of TH action in PV neurons may help understand better neurological disorders associated with alterations of TH signaling, such as hypothyroidism, resistance to THs, or Allan-Herndon-Dudley syndrome, but also more widely, neurological disorders associated with an imbalance in the excitation/inhibition ratio in the brain, including attention-deficit/hyperactivity disorder, autism, and epilepsy.